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Patnaik M.M.,Mayo Medical School | Caramazza D.,Policlinico Universitario Of Palermo | Gangat N.,Mayo Medical School | Pardanani A.,Mayo Medical School | Tefferi A.,Mayo Medical School
European Journal of Haematology | Year: 2010

Objectives: The current study was designed to identify International Prognostic Scoring System (IPSS)-independent prognostic factors in young patients with primary myelofibrosis (PMF). The study also examined the overall risk profile of long-term (>15 yr) and short-term (<5 yr) survivors. Methods: Study patients were selected from the Mayo Clinic database for PMF, and study eligibility included age <60 yr, minimum follow-up of 5 yr and availability of IPSS-relevant variables at time of diagnosis. Results: A total of 148 consecutive patients met the above-stipulated criteria. To date, 89 (60%) patients have died; 48 (32%) died within 5 yr of their diagnosis (short-term survivors). Median follow-up of patients who are alive was 9 yr (range 5-28) with a >15-yr survival documented in 16 patients (long-term survivors). Multivariable analysis identified unfavorable IPSS category (intermediate-2/high risk), age >50 yr and platelet count <100 × 109/L as independent predictors of inferior survival (P < 0.01). Median survival in the absence of all three risk factors was approximately 18 yr and was shortened to 7 and 1.6 yr in the presence of 1 or ≥2 risk factors, respectively (P < 0.01). Among long-term survivors, 69% were age ≤50 yr, 100% had favorable IPSS profile and 100% displayed platelet count ≥100 × 109/L; the corresponding figures for short-term survivors were 29%, 50% and 65% (P < 0.01). Conclusions: Age and platelet count are IPSS-independent predictors of survival in young patients with PMF, and they complement the IPSS in identifying patients with very long or very short survival. © 2009 John Wiley & Sons A/S.


Ageno W.,University of Insubria | Riva N.,University of Insubria | Schulman S.,McMaster University | Beyer-Westendorf J.,University Hospital Carl Gustav Carus | And 22 more authors.
JAMA Internal Medicine | Year: 2015

IMPORTANCE: Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT). OBJECTIVE: To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted beginning May 2,2008, and completed January 30,2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee. MAIN OUTCOMES AND MEASURES: Major bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality. RESULTS: Of the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively). CONCLUSIONS AND RELEVANCE: Most patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT. Copyright 2015 American Medical Association. All rights reserved.


Tefferi A.,Mayo Medical School | Lasho T.L.,Mayo Medical School | Abdel-Wahab O.,Sloan Kettering Cancer Center | Guglielmelli P.,University of Florence | And 12 more authors.
Leukemia | Year: 2010

In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P0.04), and less likely to display complex karyotype, in blast-phase disease (P0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.2), but not IDH mutational status (P0.55; HR 1.3, 95% CI 0.5-3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P0.04) and blast-phase MPN (P0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes. © 2010 Macmillan Publishers Limited All rights reserved.


Tefferi A.,Mayo Medical School | Siragusa S.,Policlinico Universitario Of Palermo | Hussein K.,Mayo Medical School | Schwager S.M.,Mayo Medical School | And 4 more authors.
American Journal of Hematology | Year: 2010

The International Prognostic Scoring System (IPSS) and karyotype are useful tools for risk stratification in primary myelofibrosis (PMF). We examined the additional prognostic impact of red blood cell transfusion need among 254 consecutive patients (median age, 59 years). Sixty-two patients (∼24%) required transfusions at diagnosis whereas 22 (∼9%) became transfusion-dependent and 170 remained transfusion-independent during the first year postdiagnosis; after a median follow-up of 55 months, the respective median survivals were 35, 25, and 117 months (P < 0.01). Multivariable analysis confirmed the IPSS- and karyotypeindependent prognostic weight of transfusion status. Among IPSS intermediate-1 risk patients, overall median survival of 82 months was modified to 60 or 118 months, based on presence or absence of transfusion need, respectively (P < 0.01). The corresponding figures for intermediate-2/high risk patients were 30 and 64 months (P < 0.01). Documented causes of death did not include iron overload. We conclude that transfusion status in PMF downgrades or upgrades prognosis within specific IPSS categories; transfusion need is a marker of aggressive disease biology in PMF, as it is in myelodysplastic syndromes. © 2009 Wiley-Liss, Inc.


Patnaik M.M.,Mayo Medical School | Lasho T.L.,Mayo Medical School | Finke C.M.,Mayo Medical School | Gangat N.,Mayo Medical School | And 9 more authors.
Leukemia | Year: 2010

The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with myelodysplastic syndrome with isolated del(5q) (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age 70 years (P0.01), transfusion need at diagnosis (P0.04) and dysgranulopoiesis (P0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or 2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations. © 2010 Macmillan Publishers Limited All rights reserved.


Hopps E.,Policlinico Universitario Of Palermo | Valenti A.,Policlinico Universitario Of Palermo | Caimi G.,Policlinico Universitario Of Palermo
Clinical and Investigative Medicine | Year: 2011

Portopulmonary hypertension (PPHT) is a respiratory complication of portal hypertension, defined as an increase in mean pulmonary artery pressure (PAP) of > 25 mmHg with an increase in pulmonary vascular resistance of > 240 dyn.s/cm-5 and a normal pulmonary capillary wedge pressure (<15 mmHg), which often occurs in subjects with liver cirrhosis. Histopathological features of PPHT are endothelial and smooth-muscle cell proliferation and fibrosis leading to luminal obstruction in the resistance arteries. The pathogenesis of PPHT may result from an imbalance between vasoconstrictor and vasodilating factors. The most common pulmonary symptom is exertional dyspnea; fatigue, chest pain and syncope occur more often at an advanced stage. Edema, ascites and prominent jugular veins are signs of both decompensated hepatic cirrhosis and right ventricular failure. Right heart catheterisation is the gold standard for the diagnosis and defines PPHT in mild disease with PAP less than 35 mmHg, moderate disease with PAP between 35 and 45 mmHg, and severe disease with PAP of 45 mmHg or higher. The medical treatment of portopulmonary hypertension is based on the treatment of other forms of pulmonary arterial hypertension, including vasomodulating pharmacologic agents. Liver transplantation is accompanied by high risk of mortality, generally due to acute right ventricular failure and cardiovascular collapse. The prognosis of PPHT is poor with mean survival of 15 months. © 2011 CIM.


Caramazza D.,Policlinico Universitario Of Palermo | Hussein K.,Mayo Medical School | Siragusa S.,Policlinico Universitario Of Palermo | Pardanani A.,Mayo Medical School | And 3 more authors.
European Journal of Haematology | Year: 2010

Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype-phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL-negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12→1q32 in PV, 1q21-32→1q32-44 in post-PV MF or PMF), deletions (e.g. 1p13-36→pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21- 25;p21.3-23), and other partner chromosomes involving 1q10/1p11 and 1q21-25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21-1q32 and 1p11-13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN. © 2009 John Wiley & Sons A/S.


Vaidya R.,Mayo Medical School | Caramazza D.,Policlinico Universitario Of Palermo | Begna K.H.,Policlinico Universitario Of Palermo | Gangat N.,Mayo Medical School | And 4 more authors.
Blood | Year: 2011

Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis.Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival. © 2011 by The American Society of Hematology.


Tefferi A.,Mayo Medical School | Tefferi A.,Policlinico Universitario Of Palermo | Vaidya R.,Mayo Medical School | Vaidya R.,Policlinico Universitario Of Palermo | And 8 more authors.
Journal of Clinical Oncology | Year: 2011

Purpose: Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance Patients and Methods: Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines Results: In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1 β (IL-1β), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-α), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, hepatocyte growth factor (HGF), FN-γ-inducible protein 10 (IP-10), monokine induced by IFN-γ (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-γ levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P <.001), IL-2R (P <.001), IL-12 (P <.001), IL-15 (P =.001), and IP-10 (P =.003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL-8, which was also the only cytokine associated with ≥ 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP-10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1β, and JAK2V617F. A two-cytokine (IL-8/IL-2R)-based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories Conclusion: This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response © 2011 by American Society of Clinical Oncology.


Caramazza D.,Policlinico Universitario Of Palermo | Begna K.H.,Mayo Medical School | Gangat N.,Mayo Medical School | Vaidya R.,Mayo Medical School | And 5 more authors.
Leukemia | Year: 2011

We have previously identified sole 9, 13q- or 20q-, as favorable and sole 8 or complex karyotype as unfavorable cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), 5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2-4.3; P0.0001). Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of cytogenetic-risk categorization and also identified thrombocytopenia (platelets 100 × 109 /l) as another independent predictor of inferior survival (P0.0001). A similar multivariable analysis showed that karyotype (P0.001) and platelet count (P0.04), but not IPSS (P0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable versus favorable karyotype were 46 and 7% (HR: 5.5, 95% CI: 2.5-12.0; P0.0001). This study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF. © 2011 Macmillan Publishers Limited All rights reserved.

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